As the population continues to age, the incidence of dementia is dramatically increasing, resulting in an urgent need to identify risk factors for abnormal brain aging and dementia. Insulin resistance is associated with an increased risk for dementia and the proliferation of Alzheimer's disease (AD) related pathology. The prevalence of insulin resistance is growing in parallel with the increased incidence of Diabetes Mellitus type 2 and older aged adults. However, because insulin resistance is preventable and often times reversible, it may offer a pathway for intervention in the cognitive aging process. Peripheral vasculature research suggests insulin resistance is related to decreased vascular reactivity;however the association between insulin resistance and vasoreactivity in the brain has not yet been investigated. It is unknown if insulin resistance and cerebral vasoreactivity are related to cognitive function in older adults, particularly those elders at greatest risk for cognitive declin (i.e., with mild cognitive impairment (MCI)). The proposed study will cross-sectionally examine relations between insulin resistance and cerebral vasoreactivity among older adults with MCI, as well as in cognitively normal elders, to provide important information for developing novel strategies for interventions to delay cognitive progression. The study uses an innovative neuroimaging method to capture cerebral vasoreactivity by employing a hypercapnic breath holding challenge during a duel arterial spin labeling MRI and resting state fMRI sequence. The proposed study leverages the rich resources of the Vanderbilt Memory &Alzheimer's Center, the Vanderbilt University Institute of Imaging Science, and the Vanderbilt Institute for Clinical & Translational Research to test the hypothesis that associations between insulin resistance and cognitive impairment in MCI are mediated by compromised vasoreactivity. A parallel training plan will help the applicant develop skills and knowledge in the study of modifiable risk factors for cognitive aging. Collectively, the research and training activities associated with this study will serve as a springboard for the applicant's independent research program.

Public Health Relevance

The incidence of dementia is dramatically increasing and in the absence of effective therapies there is an urgent need to identify risk factors to inform prevention strategies. Insulin resistance may have an adverse impact on cerebrovascular reactivity, which may relate to poorer cognitive outcomes. Given that insulin resistance is preventable and often reversible, the proposed project will test hypotheses to support development of novel strategies for possible interventions in the progression of dementia.